During T cell development, autoreactive T cells are eliminated in the thymus through a mechanism known as clonal deletion. However, T cells which recognize self-antigens not expressed intrathymically are not deleted and represent a potential danger. Our studies have focused on understanding the pathogenesis of the autoimmune state, the role of cytokines in mediating autoimmune tissue damage, and the treatment of established autoimmune diseases by modulation of the cytokine inducing phenotype of the disease inducing T cells: 1) Thymectomy of three day old mice (3dTx) is followed by the development of organ-specific autoimmune diseases. We have identified the target antigen recognized by CD4+ T cells present in BALB/c animals with gastritis and have definitively demonstrated that CD4+ T cells react with the major proton pump of gastric parietal cell, the H/K ATP'ase. H/K ATP'ase reactive T cell clones derived from animals with gastritis can transfer disease to immunocompromised recipients. 2) We have identified a unique population of suppressor T cells which are CD4+, IL-2 receptor+ which prevent autoantigen-specific T cells which are present in normal animals from producing disease. Depletion of the CD4+, IL-2R+ cells from normal populations abrogates their ability to inhibit disease when transferred into d3Tx recipients; furthermore, transfer of the depleted cells to nu/nu recipients results in severe autoimmune disease. 3) Inbred strains of mice exhibit a spectrum of susceptibility to induction of autoimmune diseases including experimental allergic encephalomyelitis (EAE). Detailed studies of B10.S mice which are resistant to the development of EAE demonstrated that this resistance was secondary to the failure of myelin basic protein (MBP) specific T cells to develop into Th1 cells which produce interferon gamma (IFNgamma). Induction of IFNgamma production by treatment of B10.S T cells with IL-12 lead to the development of encephalitogenic T cell populations. These results suggest that the association between intercurrent infections and presentation or relapses of autoimmune diseases may be secondary to IL-12 production in response to pathogens. On the other hand, our data support the view that antagonists to IL-12 may have therapeutic value in the treatment of inflammatory autoimmune diseases by inhibiting the activation and/or action of Th1 T cells.